1) Field of the Invention
The present invention relates to compounds of the formula I and their physiologically tolerable salts. The present invention also relates to pharmaceutical preparations comprising such compounds, their preparation and use as medicaments, in particular as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the treatment or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies, such as, for example, diabetic retinopathy, and as vitronectin receptor antagonists for the treatment and prophylaxis of illnesses which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes. The invention furthermore relates to the use of the compounds of the formula I and their physiologically tolerable salts and pharmaceutical preparations comprising such compounds as medicaments for the alleviation or cure of illnesses which are caused at least partially by an undesired extent of bone resorption, angiogenesis, or proliferation of cells of the vascular smooth musculature.
2) Description of Related Art
Human bones undergo a continuous dynamic renovation process which involves bone resorption and bone formation. These processes are controlled by types of cell specialized for this. Bone formation is based on the deposition of bone matrix by osteoblasts, bone resorption is based on the degradation of bone matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are polynuclear cells having a diameter of up to 400 xcexcm, which remove bone matrix. Activated osteoclasts accumulate on the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called xe2x80x9csealing zonexe2x80x9d, the region between their cell membrane and the bone matrix. The acid environment and the proteases bring about the degradation of the bone.
Studies have shown that the accumulation of osteoclasts on the bone is controlled by integrin receptors on the cell surface of osteoclasts.
Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor xcex1IIbxcex23 on the blood platelets and the vitronectin receptor xcex1Vxcex23. The vitronectin receptor xcex1Vxcex23 is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor xcex1Vxcex23 which is expressed on the osteoclast membrane controls the process of accumulation on the bone and bone resorption and thus contributes to osteoporosis.
xcex1Vxcex23 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and co-workers describe RGD peptides and an anti-vitronectin receptor antibody (23C6), which inhibit tooth destruction by osteoclasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. describe echistatin, an RGD peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast attachment to the bone. Fischer et al. (Endocrinology, 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo.
The vitronectin receptor xcex1Vxcex23 on human cells of the vascular smooth musculature of the aorta stimulates the migration of these cells into the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157) show that antibodies against xcex1Vxcex23or xcex1Vxcex23 antagonists can bring about a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Chersh et al. (Science 1995, 270, 1500) describe anti-xcex1Vxcex23 antibodies or xcex1Vxcex23 antagonists which inhibit bFGF-induced angiogenesis processes in the rat eye, which could be useful therapeutically in the treatment of retinopathies.
The Patent Application WO 94/12181 describes substituted aromatic or nonaromatic ring systems and WO 94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-518 586 and EP-A-528 587 disclose aminoalkyl- or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO 96/100574 describes benzodiazepines, and WO 96/100730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists.
One object of the present invention is to provide compounds and their pharmacologically tolerable salts capable of being used as inhibitors of bone resorption by osteoclast, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the treatment or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies and as vitronectin receptor antagonists for the treatment and prophylaxis of illnesses which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes. Another object of the invention is to provide compounds which can be used as carriers for active compounds in order to transfer the active compounds specifically to the site of action.
Another object of the invention is to provide a pharmaceutical preparation which includes the compound of the present invention. Still another object of the invention is to provide methods for the production of the compound of the present invention. Still another object of the present invention is to provide methods for the treatment of the conditions described above.
In accomplishing the foregoing objects, there has been provided according to one aspect of the present invention, cycloalkyl derivatives of the formula I
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83I
in which:
A is a direct bond, (C1-C8)-alkanediyl, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)Sxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94Sxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94, (C3-C12) xe2x80x94cycloalkanediyl, xe2x80x94CECxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94(C5-C14)xe2x80x94arylene-C(O)xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94(C5-C14)-arylene-, xe2x80x94COxe2x80x94, xe2x80x94(C5-C14)-arylene-COxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94SO2xe2x80x94NR2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94(C5-C14)xe2x80x94arylene-S(O)nxe2x80x94, which in each case can be mono- or disubstituted by (C1-C8)-alkanediyl, such as, for example, xe2x80x94(C1-C8)xe2x80x94alkanediyl xe2x80x94COxe2x80x94NR2xe2x80x94(C1-C8)xe2x80x94alkanediyl, xe2x80x94(C1-C8)-alkanediyl-COxe2x80x94NR2xe2x80x94(C1-C8)-alkanediyl;
B is a direct bond, (C1-C10)-alkanediyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, which in each case can be mono- or disubstituted by (C1-C8)-alkanediyl, such as, for example, xe2x80x94CH2xe2x80x94CR2xe2x95x90CR3xe2x80x94;
D is a direct bond, (C1-C8)-alkanediyl, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, or xe2x80x94CH(OH)xe2x80x94, which in each case can be mono- or disubstituted by (C1-C8)-alkanediyl;
E is a 6-membered aromatic ring system, which optionally contains up to 4 nitrogen atoms and is optionally substituted by 14 identical or different radicals from the group consisting of R2, R3, fluorine, Cl, Br, I, NO2, and OH;
F is defined as D;
G is 
Y is a direct bond or xe2x80x94NR2xe2x80x94;
R1 is R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94, or a 4-10xe2x80x94membered mono- or polycyclic aromatic or nonaromatic ring system, which can optionally contain 1-4 heteroatoms from the group consisting of N, O and S and can optionally be monosubstituted or polysubstituted by substituents from the group consisting of R11, R12, R13 and R14;
R2, R3 independently of one another are H, (C1-C10)-alkyl which is optionally mono- or polysubstituted by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkanediyl, (C5-C14)-aryl, (C1-C14)-aryl-(C1-C8)-alkanediyl, H2N, (R8O)R8NR7, R8OR7, R8OC(O)R7, R8xe2x80x94(C5-C14)-arylene-R7, R8OR7, H8xe2x80x94(C5-C14)-arylene-R7,R8R8NR7, HOxe2x80x94(C1-C8) -alkanediyl-NR8R7, R8R8NC(O)R7, R8C(O)NR8R7, R8C(O)R7, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94NR8xe2x80x94 or (C1-C18)-alkylcarbonyloxy-(C1-C6)xe2x80x94alkanediyloxycarbonyl;
R4 is (C10-C18)-cycloalkyl, (C10-C18)-cycloalkyl-(C1-C8)-alkanediyl, it being possible for the cycloalkyl radicals to be mono- or polycyclic, saturated or mono- or polyunsaturated and to be substituted as described in the case of R6, or R6OR7, R6CO2R7, R6OC(O)R7, R6xe2x80x94(C5-C14)-arylene-R7, R6N(R2)R7, R6R8NR7, R6N(R2)C(O)OR9, R6S(O)nN(R2)R7, R6OC(O)N(R2)R7, R6C(O)N(R2)R7, R6N(R2)C(O)N(R2)R7, R6N(R2)S(O)N(R2)R7, R6S(O)nR7, R6SC(O)N(R2)R7, R6C(O)R7, R6N(R2)C(O)R7, R6N(R2)S(O)nR7;
R5 is H, fluorine, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C3-C12)-cycloalkyl-(C1-C8)-alkanediyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkanediyl, it being possible for the alkyl radicals to be mono- or polysubstituted by fluorine;
R6 is (C10-C18)-cycloalkyl, (C10-C18)-cycloalkyl-(C1-C8)-alkanediyl, it being possible for the cycloalkyl radicals to be mono- or polycyclic, saturated or mono- or polyunsaturated, and mono- or polysubstituted by (C1-C10)-alkyl which is optionally mono- or poly-substituted by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkanediyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkanediyl, (C1-C8)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkanediyloxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkanediyloxy, NH2, mono- or di-(C1-C8-alkyl)-amino, (C5-C14)-aryl-(C1-C8)-alkanediylamino, (C5-C14)-arylamino, xe2x95x90O, xe2x95x90S, NO2, OH, fluorine, Cl, Br, or I;
R7 is a direct bond or (C1C8)-alkanediyl;
R8 is H, (C1C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkanediyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkanediyl, it being possible for the alkyl radicals to be mono- or polysubstituted by fluorine;
R9 is C(O)R10, C(S)R10, S(O)n,R10, P(O)(R10)n or a four- to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O, S, such as, for example, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiadiazolyl;
R10 is OH, (C1-C8)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkanediyloxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkanediyloxy, (C5-C14)-aryl-(C1-C8)-alkanediylcarbonyloxy-(C1-C5)-alkanediyloxy, NH2, mono- or di-(C1-C8-alkyl)-amino, (C5-C14)-aryl-(C1-C8)-alkanediylamino, (C1-C8)-dialkylaminocarbonylmethylenoxy, (C5-Cl14)-aryl-(C1-C8)-dialkylaminocarbonylmethylenoxy or (C5-C14)-arylamino or a radical of an L- or D-amino acid;
R11, R12, R13, R14 independently of one another are H, (C1-C10)-alkyl, which is optionally mono- or polysubstituted by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkanediyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkanediyl, H2N, (R8O)R8NR7, R8OR7, R8OC(O)R7, R8R8NR7, R8xe2x80x94(C5-C14)-arylene-R7, HOxe2x80x94(C1-C8)-alkanediyl-N(R2)R7, R8N(R2)C(O)R7, R8N(R2)C(O)R7, R8C(O)N(R2)R7, R8C(O)R7, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, xe2x95x90O, xe2x95x90S;
n is 1 or 2;
q is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in any ratio; and their physiologically tolerable salts.
According to another aspect of the present invention, there has been provided a pharmaceutical preparation comprising at least one compound of the formula I and/or a physiologically tolerable salts thereof and at least one pharmaceutically innocuous excipient and/or additive.
According to still another aspect of the present invention, there has been provided a process for the preparation of a compound of the formula I,
R13xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83I, 
in which F is xe2x80x94C(O)NR2xe2x80x94 and R1, R2, Y, A, B, D, E and G are defined as above, which comprises carrying out a fragment condensation with a compound of the formula II
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Mxe2x80x83xe2x80x83II, 
where M is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl or activated carboxylic acid derivatives and R1, Y, A, B, D and E have the abovementioned meaning, and HNR2xe2x80x94G, in which R2 and G are as defined above.
According to yet another aspect of the present invention, there has been provided a process for the preparation of a compound of the formula I,
R13xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Oxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83I, 
in which R1xe2x80x94Yxe2x80x94Axe2x80x94 is 
or a cyclic acylguanidine of the type 
and R2, R3, B, D, E, F and G are defined as above, which comprises reacting a compound of the formula III
Q(O)Cxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83III
in which Q is an easily nucleophilically substitutable leaving group and B, D, E, F and G are as defined above, with the appropriate guanidine (derivative) of the type 
or the cyclic guanidine (derivative) 
in which R2 and R3 are as defined above.
According to another aspect of the present invention, there has been provided a method for inhibiting bone resorption by osteoclasts, inhibiting tumor growth and tumor metastasis, reducing inflammation, treating or preventing cardiovascular disorders, for treating or preventing nephropathies and retinopathies or for the treatment and prevention of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes, comprising administering a therapeutically effective amount of the compound of the formula I and/or a physiologically tolerable salt thereof to a human or animal in need thereof.
Further objects, features and advantages of the present invention will become apparent from the detailed description of preferred embodiments which follows.
The alkyl radicals occurring in the substituents of the compound of formula I can be straight-chain or branched, saturated or mono- or polyunsaturated. The same applies to radicals derived therefrom, such as, for example, alkoxy.
Cycloalkyl radicals in R2, R3, R5, R8 and R11-R14 can be mono-, bi- or tricyclic.
Monocyclic cycloalkyl radicals in R2, R3, R5, R8 and R11-R14 can include, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, which, however, can also be substituted by, for example, (C1-C4)-alkyl.
Examples of substituted cycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. Examples of parent substances of monocyclic (C10-C18)-cycloalkyl radicals in R4 and R6 are, for example, cyclodecane or cyclododecane.
Bicyclic and tricyclic cycloalkyl radicals in R2, R3, R5, R8 and R11-R14 can be unsubstituted or substituted in any desired suitable positions by one or more oxo groups and/or one or more identical or different (C1-C4)-alkyl groups, e.g. methyl or isopropyl groups, preferably methyl groups. Bicyclic and tricyclic (C10-C18)-cycloalkyl radicals in R4 and R6 can be substituted as described there. The free bond of the bi- or the tricyclic radical can be located in any desired position in the molecule; the radical can thus be bonded via a bridgehead atom or an atom in a bridge. The free bond can also be located in any desired stereochemical position, for example in an exo- or an endo-position.
An example of a bicyclic ring system is decalin (decahydronaphthalene), an example of a system substituted with an oxo group is 2-decalone.
Examples of parent substances of tricyclic systems are twistane (=tri-cyclo[4.4.0.03.8]decane), adamantane (=tricyclo[3.3.1.13.7]decane), noradamantane (=tricyclo[3.3.1.03.7]nonane), tricyclo[2.2.1.02.6]heptane, tricyclo[5.3.2.04.9]dodecane, tricyclo[5.4.0.02.9]undecane or tricyclo[5.5.1.3.11]tridecane.
Examples of parent substances of tricyclic (C10-C18)-cycloalkyl radicals in R4 and R6 are twistane (=tricycio[4.4.0.03.8]decane), adamantane (=tricyclo[3.3.1.13.7]decane), noradamantane (=tricyclo[3.3.1.03.7]-nonane), tricyclo[5.3.2.04.9]dodecane, tricyclo[5.4.0.02.9]undecane or tricyclo[5.5.1.03.1]tridecane.
Examples of 6-membered aromatic ring systems are phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, tetrazinyl.
Aryl is, for example, phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, 1-naphthyl, 2-naphthyl and in particular phenyl being preferred. Aryl radicals, in particular phenyl radicals, can be mono- or polysubstituted, preferably mono-, di- or trisubstituted, by identical or different radicals from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl, (R17O)2P(O)xe2x80x94 and (R17O)2P(O)xe2x80x94Oxe2x80x94, where R17 is H, (C1-C10)-alkyl, (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl.
In monosubstituted phenyl radicals, the substituent can be located in the 2-, the 3- or the 4-position, with the 3- and the 4-position being preferred. If phenyl is disubstituted, the substituents can be in the 1,2-, 1,3- or 1,4-position relative to one another. Preferably, in disubstituted phenyl radicals the two substituents are arranged in the 3- and the 4-position. relative to the linkage site.
Aryl groups can furthermore be mono- or polycyclic aromatic ring systems in which 1 to 5 carbon atoms can be replaced by 1 to 5 heteroatoms, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, xcex2-carbolinyl, or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. These heterocycles can be substituted by the same substituents as the abovementioned carbocyclic aryl systems.
In the series of these aryl groups, mono- or bicyclic aromatic ring systems having 1-3 heteroatoms from the group consisting of N, O, S, are preferred, which can be substituted by 1-3 substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, Cl, NO2, NH2, trifluoromethyl, OH, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzyl.
Particularly preferred in this case are mono- or bicyclic aromatic 5-10-membered ring systems having 1-3 heteroatoms from the series N, O, S, which can be substituted by 1-2 substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyl or benzyloxy.
L- or D-amino acids can be natural or unnatural amino acids. xcex1-Amino acids are preferred. Examples which may be mentioned are (cf. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974):
Aad, Abu, xcex3Abu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94AIa, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab. Dadd, Dap, Dapm, Dasu, Dien, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94Lys, Met, Mim, Min, nArg, Nie, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, 2-(p-chlorophenyl)aminoacetic acid.
The amino acids can furthermore include:
pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicycto[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonane-3-carboxylic acid; 2-azaspiro[4.5]decane-3-carboxyl[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.16.9]decane-3carboxylic acid; decahydrocyclohepta-[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid, all of which can be optionally substituted (see following formulae): 
The heterocycles on which the abovementioned radicals are based are disclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No. 4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488: EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.
The amino acids can furthermore also be present as esters or amides, such as, for example, the methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethyl amide, semicarbazide or xcfx89-amino-(C2-C8)-alkyl amide.
Functional groups of the amino acids can be present in protected form. Suitable protective groups such as, for example, urethane protective groups, carboxyl protective groups and side chain protective groups are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 and in Bullesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. The following may be mentioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, lboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
Physiologically tolerable salts of the compounds of the formula I are, in particular, pharmaceutically utilizable or nontoxic salts. Such salts are formed, for example, from compounds of the formula I which contain acidic groups, e.g. carboxyl, with alkali metals or alkaline earth metals, such as, for example, Na, K, Mg and Ca, and with physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine or tris(2-hydroxyethyl) amine. Compounds of the formula I which contain basic groups, e.g. an amino group, an amidino group or a guanidino group, form salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
The compounds of the formula I according to the invention can contain optically active carbon atoms which independently of one another can have R or S configuration and can thus be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomer mixtures or diastereomer mixtures. The present invention relates both to pure enantiomers and enantiomer mixtures and to diastereomers and diastereomer mixtures. The invention covers mixtures of two stereoisomers and of more than two stereoisomers of the formula I and all ratios of stereoisomers in the mixtures.
If A, D and F independently of one another are xe2x80x94CR2xe2x95x90CR3xe2x80x94, the compounds of the formula I according to the invention can be present as E/Z isomer mixtures. The present invention relates to both pure E and Z isomers and to mixtures of E/Z isomers in all ratios. Diastereomers, including E/Z isomers, can be separated into the individual isomers by chromatography. Racemates can either be separated into the two enantiomers by chromatography on chiral phases or by resolution.
The compounds of the formula I according to the invention can moreover contain mobile hydrogen atoms, i.e. be present in various tautomeric forms. The present invention also relates to these tautomers.
Preferred compounds of the formula I are those in which:
A is a direct bond, (C1-C6)-alkanediyl, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)nxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94N R2xe2x80x94, xe2x80x94N R2xe2x80x94C(S)xe2x80x94Oxe2x80x94, NR2xe2x80x94C(S)xe2x80x94Sxe2x80x94, xe2x80x94N R2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94, (C3-C8)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94,xe2x80x94NR2xe2x80x94C(O)xe2x80x94, C(O)xe2x80x94NR2xe2x80x94, xe2x80x94(C5-C12)-arylene-C(O)xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94(C5-C12)-arylene-, xe2x80x94COxe2x80x94, xe2x80x94(C5-C12)-arylene-COxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94SO2xe2x80x94NR2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94(C5-C12-arylene-S(O)nxe2x80x94, which in each case can be mono- or disubstituted by (C1-C8)-alkanediyl;
B is a direct bond, (C1-C8)-alkanediyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94, which in each case can be mono- or disubstituted by (C1-C8)-alkanediyl;
D is a direct bond, (C1-C8)-alkanediyl or xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, which in each case can be mono- or disubstituted by (C1-C6)-alkanediyl;
E is a 6-membered aromatic ring system, which optionally contains 1 or 2 nitrogen atoms and is optionally substituted by 1-3 identical or different radicals from the group consisting of R2, R3, fluorine, Cl and OH;
F is defined as D;
G is 
Y is a direct bond or xe2x80x94NR2xe2x80x94;
R1 is R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, NR2xe2x80x94, or 4-10-membered mono- or polycyclic aromatic or nonaromatic ring system which can optionally contain 1-4 heteroatoms from the group consisting of N, O and S and can optionally be monosubstituted or polysubstituted by substituents from the group consisting of R11, R12, R13 and R14;
R2, R3 independently of one another are H, (C1-C8)-alkyl which is optionally mono- or polysubstituted by fluorine, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C3-C6)-alkanediyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkanediyl, H2N, (R8O)R8), NR7, R8OR7, R8OC(O)R7, R8xe2x80x94(C5-C12)-arylene-R7, R8R8Nxe2x80x94, HOxe2x80x94(C1-C8)-alkanediyl-NR8R7, R8R8R8NC(O)R7, R8C(O)NR8R7, R8C(O)R7, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94NR8xe2x80x94 or (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkanediyloxycarbonyl;
R4 is (C10-C16)-cycloalkyl, (C10-C16)-cycloalkyl-(C1-C8)-alkanediyl, it being possible for the cycloalkyl radicals to be mono- or polycyclic, saturated or mono- or polyunsaturated and to be substituted as described in the case of R6, or R6OR7, R6SR7, R6CO2R7, R6OC(O)R7, R6xe2x80x94(C5-C12)-arylene-R7, R6R8NR7, R6N(R2)C(O)OR7, R6S(O)nN(R2)R7, R6OC(O)N(R2)R7, R6C(O)N(R2)R7, R6N(R2)C(O)N(R2)R7, R6N(R2)S(O)nN(R2)R7, R6S(O)nR7, R6SC(O)N(R2)R7, R6C(O)R7, R6N(R2)C(O)R7, R6N(R2)S(O)nR7;
R5 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkanediyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C6)-alkanediyl, it being possible for the alkyl radicals to be mono- or polysubstituted by fluorine;
R6 is (C10-C16)-cycloalkyl, (C10-C16)-cycloalkyl-(C1-C6)-alkanediyl, it being possible for the cycloalkyl radicals to be bi- or tricyclic, saturated or mono- or polyunsaturated, and mono- or polysubstituted by (C1-C8)-alkyl, which is optionally mono- or polysubstituted by fluorine, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C6)-alkanediyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C6)-alkanediyl, (C1-C6)-alkoxy, (C5-C10)-aryloxy, (C5-C10)-aryl-(C1-C6)-alkanediyloxy, NH2, mono- or di-(C1-C6)-alkyl)-amino, xe2x95x90O, OH, fluorine or Cl;
R7 is a direct bond or (C1-C6)-alkanediyl;
R8 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkanediyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkanediyl, it being possible for the alkyl radicals to be mono- or polysubstituted by fluorine;
R9 is C(O)R10, C(S)R10, S(O)nR10, P(O)(R10)n or a four to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group consisting of N, O, S;
R10 is OH, (C1-C6)-alkoxy, (C5-C12)-aryl-(C1-C6)-alkanediyloxy, (C5-C12)-aryloxy, (C1-C6)-alkylcarbonyloxy-(C1-C4)-alkanediyloxy, (C5-C12)-aryl-(C1-C6)-alkanediylcarbonyloxy-(C1-C6)-alkanediyloxy, NH2, mono- or di-(C1-C6-alkyl)-amino, (C5-C12)-aryl-(C1-C6)-alkanediylamino, (C1-C6)-dialkylaminocarbonyl-methylenoxy;
R11, R12, R13, R14 independently of one another are H, (C1-C8)-alkyl, which is optionally mono- or polysubstituted by fluorine, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkanediyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkanediyl, H2N, (R8O)R8NR7, R8OR7, R8OC(O)R7, R8xe2x80x94(C5-C12)-arylene-R7, R8R8NR7, HOxe2x80x94(C1-C8)-alkyl-N(R2)R7, R8N(R2)C(O)R7, R8C(O)N(R2)R7, R8C(O)R7, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR3)xe2x80x94NR2, xe2x95x90O, xe2x95x90S;
n is 1 or 2;
q is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in any ratio; and their physiologically tolerable salts.
Particularly preferred compounds of the formula I are those in which:
A is a direct bond, (C1-C6)-alkanediyl, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94, (C3-C6)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, which in each case can be mono- or disubstituted by (C1-C6)-alkanediyl;
B is a direct bond, (C1-C6)-alkanediyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94, which can be mono- or disubstituted by (C1-C6)-alkanediyl;
D is a direct bond, (C1-C6)-alkanediyl or xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, which in each case can be mono- or disubstituted by (C1-C6)-alkanediyl;
E is phenylene or pyridinediyl which is optionally substituted by 1-3 identical or different radicals from the group consisting of R2 and R3;
F is a direct bond, (C1-C6)-alkanediyl, or xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR2, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, which in each case can be mono- or disubstituted by (C1-C6)-alkanediyl;
G is 
Y is a direct bond or xe2x80x94NHxe2x80x94;
R1 is R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, 
R2, R3 independently of one another are H, (C1-C6)-alkyl which is optionally mono- or polysubstituted, preferably 1-6 times, by fluorine, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkanediyl, (C5-C10)-aryl-(C5-C10)-aryl-(C1-C4)-alkanediyl, H2N, R8OR7, R8xe2x80x94(C5C10)-arylene-R7, R8R8NR7, R8NHC(O)R7, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94;
R4 is (C10-C14)-cycloalky, (C10-C14)-cycloalkyl-(C1-C6)-alkanediyl, it being possible for the cycloalkyl radicals to be bi- or tricyclic, and to be substituted 1-3 times by (C1-C6)-alkyl, trifluoromethyl, pentafluoroethyl, phenyl, benzyl, (C1-C6)-alkoxy, phenoxy, benzyloxy, NH2, xe2x95x90O or mono- or di-(C1-C6-alkyl)-amino; or R6OR7, R6CO2R7, R6OC(O)R7, R6NHR7, R6R8NR7, R6NHC(O)OR7, R6S(O)nNHR7, R6C(O)NHR7, R6C(O)NHR7, R6C(O)R7, R6NHC(O)NHR7, R6NHC(O)R7;
R5 is H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C6)-alkanediyl, trifluoromethyl, pentafluoroethyl, phenyl, benzyl;
R6 is (C10-C14)-cycloalkyl, (C10-C14)-cycloalkyl-(C1-C8)-alkanediyl, it being possible for the cycloalkyl radicals to be bi- or tricyclic, and to be substituted 1-3 times by (C1-C6)-alkyl, trifluoromethyl, pentafluoroethyl, phenyl, benzyl, (C1-C6)-alkoxy, phenoxy, benzyloxy, NH2, xe2x95x90O or mono- or di-(C1-C6-alkyl)-amino;
R7 is a direct bond or (C1-C6)-alkanediyl;
R8 is H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkanediyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkanediyl, it being possible for the alkyl radicals to be substituted by 1-6 fluorine atoms;
R9 is C(O)R10;
R10 is OH, (C1-C5)-alkoxy, (C5-C10)-aryl-(C1-C6)-alkanediyloxy, (C5-C10)-aryloxy, (C1-C6)-alkylcarbonyloxy-(C1-C4)-alkanediyloxy, (C5-C10)-aryl-(C1-C4)-alkanediylcarbonyloxy-(C1-C4)-alkanediyloxy, NH2, mono- or di-(C1-C6-alkyl)-amino;
R11 is H, (C1-C6)-alkyl which is optionally mono- or polysubstituted by fluorine, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkanediyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkanediyl, H2N, R8OR7, R8OC(O)R7, R8xe2x80x94(C5-C10)-arylene-R7, R8R8NR7, R8NHC(O)R7, R8C(O)NHR7, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94, xe2x95x90O;
n is 1 or 2;
q is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in any ratio; and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
A is a direct bond, (C1-C4)-alkanediyl, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94 or xe2x80x94NR2xe2x80x94, which in each case can be mono- or disubstituted by (C1-C4)-alkanediyl;
B is a direct bond or (C1-C4)-alkanediyl;
D is a direct bond, (C1-C4)-alkanediyl or xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, which in each case can be mono- or disubstituted by (C1-C4)-alkanediyl;
E is phenylene or pyridinediyl which is optionally substituted by 1 or 2 radicals from the group consisting of R2, R3;
F is a direct bond, (C1-C6)-alkanediyl, or xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, which in each case can be mono- or disubstituted by (C1-C4)-alkanediyl;
G is 
Y is a direct bond or xe2x80x94NHxe2x80x94;
R1 is R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, 
R2, R3 independently of one another are H, (C1-C6)-alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C2)-alkanediyl, phenyl, benzyl, H2N, R8OR7, R8R8NR7, R8NHC(O)R7, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94;
R4 is (C10-C12)-cycloalkyl, (C10-C12)-cycloalkyl-(C1-C6)-alkanediyl, or R6OR7, R6R8NR7, R6NHC(O)OR7, R6S(O)nNHR7, R6OC(O)NHR7, R6C(O)NHR7, the cycloalkyl radicals preferably being 1-adamantyl or 2-adamantyl and the cycloalkylalkanediyl radicals preferably being adamantyl-1xe2x80x94(C1-C3)-alkanediyl or adamantyl-2xe2x80x94(C1-C3)-alkanediyl and it being possible for them to be substituted 1 or 2 times by (C1-C4)-alkyl, trifluoromethyl, phenyl, benzyl, (C1-C4)-alkoxy, phenoxy, benzyloxy, xe2x95x90O or mono- or di-(C1-C4-alkyl)-amino, adamantyl radicals substituted 1 or 2 times as described above or (C11-C12)-cycloalkyl radicals which are unsubstituted or substituted 1 or 2 times as described above being particularly preferred;
R5 is H, (C1-C4)-alkyl, trifluoromethyl;
R6 is (C10-C12)-cycloalkyl, (C10-C12)-cycloalkyl-(C1-C6)-alkanediyl, the cycloalkyl radicals preferably being 1-adamantyl or 2-adamantyl and the cycloalkylalkanediyl radicals preferably being adamantyl-1xe2x80x94(C1-C3)-alkanediyl or adamantyl-2xe2x80x94(C1-C3)-alkanediyl and it being possible for them to be substituted 1 or 2 times by (C1-C4)-alkyl, trifluoromethyl, phenyl, benzyl, (C1-C4)-alkoxy, phenoxy, benzytoxy, xe2x95x90O or mono- or di-(C1-C4-alkyl)-amino, adamantyl radicals substituted 1 or 2 times as described above or (C11-C12)-cycloalkyl radicals which are unsubstituted or substituted 1 or 2 times as described above being particularly preferred;
R7 is a direct bond or (C1-C6)-alkanediyl;
R8 is H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C2)-alkanediyl, (C5-C6)-aryl, (C5-C6)-aryl-(C1-C2)-alkanediyl;
R9 is C(O)R10;
R10 is OH, (C1-C6)-alkoxy, phenoxy, benzyloxy, (C1-C4)-alkylcarbonyloxy-(C1-C4)-alkanediyloxy, NH2, mono- or di-(C1-C6-alkyl)-amino;
n is 1 or 2;
q is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in any ratio;
and their physiologically tolerable salts.
Especially preferred compounds of the formula I are those in which:
A is xe2x80x94NHxe2x80x94C(O)xe2x80x94;
B is (C1-C4)-alkanediyl;
D is xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94 or a direct bond;
E is phenylene or pyridinediyl;
F is xe2x80x94CH2xe2x80x94 or xe2x80x94C(O)NHCH2xe2x80x94;
G is 
Y is a direct bond;
R1 is H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, 
R2 is H or (C1-C4)-alkyl;
R4 is R6OC(O)NHxe2x80x94;
R5 is H;
R6 is adamantyl-1xe2x80x94(C1-C3)-alkylene, adamantyl-2xe2x80x94(C1-C3)-alkylene, 1-adamantyl, 2-adamantyl, adamantyl preferably being substituted 1 or 2 times by (C1-C4)-alkyl, trifluoromethyl, phenyl, benzyl, (C1-C4)-alkoxy, phenoxy or benzyloxy, or (C11-C12)-cycloalkyl which can be substituted 1 or 2 times as above;
R9 is C(O)R10;
R10 is OH, (C1-C6)-alkoxy, phenoxy, benzyloxy or (C1-C4)-alkoxycarbonyloxy-(C1-C4)-alkanediyloxy;
in all their stereoisomeric forms and mixtures thereof in any ratio;
and their physiologically tolerable salts.
Compounds of the formula I can generally be prepared, for example in the course of a convergent synthesis, by linkage of two or more fragments which can be derived retrosynthetically from the formula I. In the preparation of the compounds of the formula I, it may generally be necessary in the course of the synthesis temporarily to block functional groups which could lead to undesired reactions or side reactions in the respective synthesis step by means of a protective group strategy suited to the synthesis problem and known to the person skilled in the art using the present specification as a guide. The method of fragment coupling is not restricted to the following examples, but is generally applicable for syntheses of the compounds of the formula I.
For example, compounds of the formula I of the type
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94C(O)NR2xe2x80x94G,
where F in the formula I is xe2x80x94C(O)NR2xe2x80x94 can be prepared by condensation of a compound of the formula II
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Mxe2x80x83xe2x80x83II,
where M is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl, activated carboxylic acid derivatives such as acid chlorides, active esters or mixed anhydrides, with HNR2xe2x80x94G. For the condensation of two fragments with formation of an amide bond, the coupling methods of peptide chemistry known per se (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974) are advantageously used. For this purpose, as a rule it is necessary to protect nonreacting amino groups present during the condensation by reversible protective groups. The same applies to carboxyl groups not participating in the reaction, which are preferably employed as (C1-C6)-alkyl, benzyl or tert-butyl esters. Amino group protection is unnecessary if the amino groups to be generated are still present as nitro or cyano groups and are formed by hydrogenation only after coupling. After coupling, the protective groups present are removed in a suitable manner. For example, NO2 groups (guanidino protection), benzyloxycarbonyl groups and benzyl esters can be removed by hydrogenation. The protective groups of the tert-butyl type are cleaved under acidic conditions, while the 9xe2x80x94fluorenylmethyloxycarbonyl radical is removed by secondary amines.
Compounds of the formula I in which R1 has the meaning indicated, Y is xe2x80x94NR2xe2x80x94 and A is xe2x80x94C(O)xe2x80x94 can be prepared, for example, by the generally known coupling methods of peptide chemistry by coupling R1xe2x80x94NR2H with HO2Cxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94G.
Compounds of the formula I where R9=SO2R10 are prepared, for example, by oxidizing compounds of the formula I where R9=SH by processes known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058 et seq.) to compounds of the formula I where R9=SO3H, from which the compounds of the formula I where R9=SO2R10(R10xe2x89xa0OH) are then prepared directly or via corresponding sulfonic acid halides by esterification or linkage of an amide bond. Oxidation-sensitive groups in the molecule, such as, for example, amino, amidino or guanidino groups are protected, if necessary, by suitable protective groups before carrying out the oxidation.
Compounds of the formula I where R9=S(O)R10 are prepared, for example, by converting compounds of the formula I where R9=SH into the corresponding sulfide (R9=Se) and then oxidizing with meta-chloroperbenzoic acid to the sulfinic acids (R9=SO2H) (cf. Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. E11/1. Georg Thieme Verlag, Stuttgart 1985, p. 618 et seq.), from which the corresponding sulfinic acid esters or amides R9=S(O)R10 (R10xe2x89xa0OH) can be prepared by methods known from the literature. Generally, other methods known from the literature can also be used for the preparation of compounds of the formula I where R9=S(O)nR10 (n=1, 2) (cf. Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, p. 618 et seq. or Vol. E11/2, Stuttgart 1985, p. 1055 et seq.).
Compounds of the formula I where R9=P(O)(R10)n (n=1, 2) are synthesized from suitable precursors by processes known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. E1 and E7, Georg Thieme Verlag, Stuttgart 1982), the synthesis method selected being suited to the target molecule.
Compounds of the formula I where R9=C(S)R10 can be prepared by processes known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. E5/1 and E5/2, Georg Thieme Verlag, Stuttgart 1985).
Compounds of the formula I where R9=S(O)nR10 (n=1, 2), P(O)(R10)n (n=1,2) or C(S)R10 can of course also be prepared by fragment coupling, such as described above, which is advisable, for example, when, for example, a (commercially available) aminosulfonic acid, aminosulfinic acid, aminophosphonic acid or aminophosphinic acid or derivatives derived therefrom, such as esters or amides, are contained in F-G of the formula I.
Compounds of the formula I in which R1xe2x80x94Yxe2x80x94Axe2x80x94 is 
or cyclic acylguanidines of the type 
can be prepared, for example, by reacting a compound of the formula III
Q(O)Cxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83III
in which Q is an easily nucleophilically substitutable leaving group, with the appropriate guanidine (derivative) of the type 
or the cyclic guanidine (derivative) of the type 
The activated acid derivatives of the formula III, in which Q is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio or methylthio 2xe2x80x94pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the carboxylic acids (Q=OH) or carbonyl chlorides (Q=Cl) on which they are based. The latter are in turn obtained in a manner known per se from the carboxylic acids (Q=OH) on which they are based, for example by reaction with thionyl chloride.
Beside the carbonyl chlorides (Q=Cl), further activated acid derivatives of the type Q(O)Cxe2x80x94 can be prepared in a manner known per se directly from the carboxylic acids (Q=OH) on which they are based, such as, for example, the methyl esters (Q=OCH3) by treating with gaseous HCl in methanol, the imidazolides (Q=1-imidazolyl) by treating with carbonyldiimidazole [cf. Staab, Angew. Chem. lnt. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides (Q=C2H5OC(O)O or TosO) with Clxe2x80x94COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent. The activation of the carboxylic acids can also be carried out with dicyclohexylcarbodiimide (DCCl) or with O-[(cyano(ethoxy-carbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (xe2x80x9cTOTUxe2x80x9d) [Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)] and other activating reagents customary in peptide chemistry. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are indicated stating source literature in J. March. Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula III with the respective guanidine (derivative) is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In this context, methanol, isopropanol or THF from 20xc2x0 C. up to the boiling temperature of these solvents have proven suitable in the reaction of the methyl esters (Q=OCH3) with the respective guanidines. In the case of most reactions of compounds of the formula III with salt-free guanidines, the reaction is advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane, dioxane. However, if a base (such as, for example, NaOH) is used, it is also possible to use water as a solvent in the reaction of compounds of the formula III with guanidines. If Q=Cl, the reaction is advantageously carried out with addition of an acid scavenger, e.g. in the form of excess guanidine (derivative) to bind the hydrohalic acid.
Compounds of the formula I in which R1xe2x80x94Yxe2x80x94Axe2x80x94 is R2xe2x80x94C(xe2x95x90NR2)xe2x80x94C(O)xe2x80x94 or a system comprising a mono- or polycycle of the type 
Compounds of the formula I in which R1xe2x80x94Yxe2x80x94A is a sulfonyl- or sulfoxylguanidine of the type R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94S(O)nxe2x80x94 (n xe2x95x901, 2) or a sulfonyl- or sulfoxylaminoguanidine of the type R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94NR2xe2x80x94S(O)nxe2x80x94 (n=1, 2) or 
are prepared by processes
known from the literature by reaction of R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2H or R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94NR2H or 
with sulfinic or sulfonic acid derivatives of the formula IV
Qxe2x80x94S(O)nxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83IV
in which Q, for example, is Cl or NH2, analogously to S. Birtwell et al., J. Chem. Soc. (1946) 491 or Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. E4, Georg Thieme Verlag, Stuttgart 1983; p. 620 et seq.
Compounds of the formula I in which R1xe2x80x94Yxe2x80x94Axe2x80x94 is R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94S(O)nxe2x80x94(n=1, 2) or R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94S(O)nxe2x80x94 (n=1, 2) or a system comprising a mono- or polycycle of the type 
(n=1, 2) can be obtained analogously.
Compounds of the formula I in which Y has the meaning indicated, A is xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)Sxe2x80x94 and R1 is R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, R2xe2x80x94C(xe2x95x90NR2)xe2x80x94 or a 4-10-membered mono- or polycyclic, aromatic or nonaromatic ring system which is specified as described above and can be substituted as described there, are prepared, for example, by reacting a compound of the formula V
Qxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83V
in which Q is HNR2xe2x80x94, HOxe2x80x94 or HSxe2x80x94, with a suitable carbonic acid derivative, preferably phosgene, diphosgene (trichloromethyl chloroformate), triphosgene (bistrichloromethyl carbonate), ethyl chloroformate, i-butyl chloroformate, bis(1-hydroxy-1-H-benzotriazolyl) carbonate or N,Nxe2x80x2-carbonyldiimidazole, in a solvent which is inert to the reagents used, preferably DMF, THF or toluene, at a temperature between xe2x88x9220xc2x0 C. and the boiling point of the solvent, preferably between 0xc2x0 C. and 60xc2x0 C. first to give a substituted carbonic acid derivative of the formula VI 
in which R is xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and Qxe2x80x2, depending on the carbonic acid derivative used, is chlorine, ethoxy, isobutoxy, benzotriazoi-1-oxy or 1-imidazolyl.
The reaction of these derivativesxe2x80x94in the case where Y is a direct bondxe2x80x94with R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2H or R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2H or, if Y is xe2x80x94NR2xe2x80x94, with R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94NR2H or R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94NR2H or with the systems comprising a mono- or polycycle of the type 
is carried out as described above in the preparation of acylguanidine (derivatives).
Compounds of the formula I in which F is xe2x80x94R2Nxe2x80x94C(O)xe2x80x94NR2xe2x80x94 or xe2x80x94R2Nxe2x80x94C(S)xe2x80x94NR2xe2x80x94 are prepared, for example, by reacting a compound of the formula VII
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94NHR2 xe2x80x83xe2x80x83Vl
with an isocyanate OCNxe2x80x94G or isothiocyanate SCNxe2x80x94G by processes known from the literature.
Compounds of the formula I, in which F is xe2x80x94C(O)NR2xe2x80x94, xe2x80x94SO2NR2xe2x80x94 or xe2x80x94C(O)Oxe2x80x94 can be prepared, for example, by reaction of
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94C(O)Q or R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94SO2Q
(Q is an easily nucleophilically substitutable leaving group, such as, for example, OH, Cl, OCH3 etc.) with HR2Nxe2x80x94G or HOxe2x80x94G by processes known from the literature.
Compounds of the formula I in which Y is a bond and R1xe2x80x94Axe2x80x94 comprises a mono- or polycycle of the type 
can be prepared, for example, by reacting a compound of the formula VIII
HR2Nxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83VIII
with a mono- or polycycle of the type 
in which X is a nucleophilically substitutable leaving
group such as, for example, halogen or SH, SCH3, SOCH3, SO2CH3 or HNxe2x80x94NO2, by processes known from the literature (see, for example, A. F. Mckay et al., J. Med. Chem. 6 (1963) 587, M. N. Buchman et al., J. Am. Chem. Soc. 71 (1949), 766, F. Jung et al., J. Med. Chem. 34 (1991) 1110 or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391).
Compounds of the formula I in which Y is a bond and R1xe2x80x94Axe2x80x94 comprises a mono- or polycycle of the type 
can be prepared, for example, by reacting a
compound of the formula VIII with a compound of the type 
in which X is a leaving group, such as, for example
xe2x80x94SCH3, by processes known from the literature (cf., for example, T. Hiroki et al., Synthesis (1984) 703 or M. Purkayastha et al., Indian J. Chem. Sect. B 30 (1991) 646).
Compounds of the formula I in which D is xe2x80x94Cxe2x89xa1Cxe2x80x94 can be prepared, for example, by reacting a compound of the formula IX
Xxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83IX
in which X is I or Br with a compound of the type R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Cxe2x89xa1CH in a palladium-catalyzed reaction, such as described, for example, in A. Arcadi et al., Tetrahedron Lett. 1993, 34, 2813 or E. C. Taylor et al. J. Org. Chem. 1990, 55, 3222.
Analogousty, compounds of the formula I in which F is xe2x80x94Cxe2x89xa1Cxe2x80x94 can be prepared, for example, by linkage of compounds of the formula X
R1xe2x80x94Yxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Xxe2x80x83xe2x80x83X
in which X is I or Br with a compound of the type HCxe2x89xa1Cxe2x80x94G in a palladium-catalyzed reaction.
Preparation processes known from the literature are described, for example, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985).
The compounds of the formula I according to the invention inhibit bone resorption by osteoclasts. Bone diseases against which the compounds according to the invention can be employed are especially osteoporosis, hypercalcemia, osteopenia, e.g. caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget""s disease.
The compounds of the formula I can furthermore be employed for the alleviation, avoidance or therapy of bone disorders which are caused by a glucocorticoid, steroid or corticosteroid therapy or by a deficiency of sex hormone(s). All these disorders are characterized by bone loss, which is based on the inequilibrium between bone formation and bone destruction.
The compounds of the formula I can furthermore be used as carriers for active compounds in order to transfer the active compounds specifically to the site of action (=drug targeting, see, for example, Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology Vol. 100, Ed. Born, G. V. R. et al., Springer Verlag). The active compounds are those which can be used for the treatment of the abovementioned diseases.
The compounds of the formula I and their physiologically tolerable salts can be administered to animals, preferably to mammals, and in particular to humans as medicaments by themselves, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral administration and which as an active constituent contain an efficaceous dose of at least one compound of the formula I or of a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives. The preparations normally contain approximately 0.5 to 90% by weight of the therapeutically active compound.
The medicaments can be administered orally, e.g. in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration can also be carried out rectally, however, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection or infusion solutions, microcapsules or rods, percutaneously, e.g. in the form of ointments or tinctures, or nasally, e.g. in the form of nasal sprays.
The pharmaceutical preparations are prepared in a manner known per se, pharmaceutically inert inorganic or organic excipients being used. For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts etc. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable excipients for the preparation of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols, etc. Suitable excipients for the production of injection solutions are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable excipients for microcapsules, implants or rods are copolymers of glycolic acid and lactic acid.
Beside the active compounds and excipients, the pharmaceutical preparations can also contain additives, such as, for example, fillers, extenders, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickening agents, diluents, buffer substances, furthermore solvents or solubilizers or agents for achieving a depot effect, and salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I or their physiologically tolerable salts; furthermore beside at least one compound of the formula I, also one or more other therapeutically active substances.
The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. In the case of oral administration, the daily dose is in general from 0.01 to 50 mg/kg, preferably 0.1 to 5 mg/kg, in particular 0.3 to 0.5 mg/kg, of bodyweight to achieve efficacious results; in the case of intravenous administration the daily dose is in general approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg, of body weight. In particular in the case of the administration of relatively large amounts, the daily dose can be divided into more than one, e.g. 2, 3 or 4, part administrations. In some cases it may be necessary, depending on individual behavior, to deviate upward or downward from the daily dose indicated.